Neuropsychological deficits in patients with cognitive complaints after COVID‐19

Abstract Background While much of the scientific focus thus far has been on cognitive sequelae in patients with severe COVID‐19, subjective cognitive complaints are being reported across the spectrum of disease severity, with recent studies beginning to corroborate patients’ perceived deficits. In response to this, the aims of this study were to (1) explore the frequency of impaired performance across cognitive domains in post‐COVID patients with subjective complaints and (2) uncover whether impairment existed within a single domain or across multiple. Methods Sixty‐three patients with subjective cognitive complaints post‐COVID were assessed with a comprehensive protocol consisting of various neuropsychological tests and mood measures. Cognitive test performance was transformed into T scores and classified based on recommended guidelines. After performing a principal component analysis to define cognitive domain factors, distributions of test scores within and across domains were analyzed. Results Results revealed pervasive impact on attention abilities, both as the singularly affected domain (19% of single‐domain impairment) as well as coupled with decreased performance in executive functions, learning, and long‐term memory. These salient attentional and associated executive deficits were largely unrelated to clinical factors such as hospitalization, disease duration, biomarkers, or affective measures. Discussion These findings stress the importance of comprehensive evaluation and intervention to address cognitive sequelae in post‐COVID patients of varying disease courses, not just those who were hospitalized or experienced severe symptoms. Future studies should investigate to what extent these cognitive abilities are recuperated over time as well as employ neuroimaging techniques to uncover underlying mechanisms of neural damage.


INTRODUCTION
After more than 1 year since the beginning of the pandemic, we have consistent evidence that the disease caused by SARS-CoV-2 infection, COVID-19, is a multisystemic syndrome (Jiang et al., 2020). This coronavirus has been shown to cause multi-organ dysfunction, affecting not only the lungs but also the heart, kidneys, gut, liver (Batlle et al., 2020;Long et al., 2020;Terpos et al., 2020), and the brain (Harapan & Yoo, 2021;Stein et al., 2021;Wei et al., 2020). Even when relatively little was known about COVID-19 symptomatology, reports of neurological complications associated with SARS-CoV-2 were published (Moriguchi et al., 2020;Ye et al., 2020); subsequently, the impact of this coronavirus on the brain has been a topic of great interest (Leonardi et al., 2020).
Although the frequency and severity of neurological symptoms associated with COVID-19 may vary to some degree according to the severity of neuroinflammation and other medical conditions (Nordvig et al., 2021;Yassin et al., 2021), recent findings show that  survivors with a wide range of disease courses, ranging from asymptomatic (Amalakanti et al., 2021) to those with severe symptoms (Negrini et al., 2021;Whiteside et al., 2021), may present with both short-and long-term cognitive deficits. In a recent review, Alnefeesi et al. (2021) assessed seven studies and concluded that COVID-19 predominantly affects long-term memory and executive functions.
To date, epidemiologic studies with large samples of patients have used screening tests for global cognition or qualitative assessments of mental status (García-Azorín et al., 2021;Raman et al., 2021;Taquet et al., 2021). While the findings from these studies serve as useful evidence in revealing general cognitive impact associated with COVID-19, results from screening tests cannot be used to address the question of specificity in cognitive deficits. Other studies with smaller sample sizes have begun to apply more comprehensive neuropsychological evaluations, providing a more detailed picture of deficits in the weeks and months following infection and/or hospital discharge. Shortterm deficits were found in attention (Almeria et al., 2020;Zhou et al., 2020), in long-term memory, attention and executive functions (Almeria et al., 2020), and in inhibitory control (Ortelli et al., 2021). Considering more long-term effects, Ferrucci et al. (2021) reported evidence of long-term memory deficits in COVID-19 patients 5 months after hospitalization and Mazza et al. (2021) found that half of their COVID-19 patient sample demonstrated executive function deficits and 30% of them showed impairments in information processing, verbal fluency, and working memory at a 3-month follow-up. In contrast to these findings, Mattioli et al. (2021) found no evidence of any cognitive impairment in patients with COVID-19 compared to a group of control participants 4 months after SARS-CoV-2 infection.
It is also important to define the nature of deficits in terms of single versus multiple-domain impact. In making this distinction, the existence of deficits within or across domains can begin to indicate how widespread the impacts on underlying cognitive mechanisms are.
As research from neuroimaging studies in COVID-19 survivors has thus far shown a heterogeneous picture of brain damage, the presence of multiple-domain deficits would further confirm the diverse effects of COVID-19 on the brain. Within the current literature, one line of evidence is indicating that medial temporal structures and hippocampus (Ladopoulos et al., 2021) are affected; given this, memory-related deficits would then be expected, mainly for the consolidation of new information. Indeed, findings from studies that investigated neuropsychological impairments in COVID-19 reveal long-term memory deficits (Almeria et al., 2020;Ferrucci et al., 2021). Other studies have found changes in metabolism at frontoparietal level (Hosp et al., 2021), which would suggest potential impairments in the attentional networks.
Linking this to neuropsychological findings, deficits of attention and executive functions are indeed reported in many studies (Almeria et al., 2020;Ortelli et al., 2021;Zhou et al., 2020). With these two emerging links between brain and behavior, it is crucial to know the extent to which patients have both memory and executive function deficits in order to determine whether they could be explained by the same processes.
In the present study, we focus on investigating a sample of outpatients who reported subjective cognitive complaints after SARS-CoV-2 infection. Using tests spanning across different cognitive domains, the study sought to determine which cognitive abilities are most affected in this population. Addressing remaining uncertainties outlined above, we had two aims for this study: (1) to analyze the frequency of deficits for specific cognitive domains and (2) to discern the frequency of singleand multiple-domain impairments and to understand which combinations of deficits were a specific feature of post-COVID-19 cognitive impairment. Additionally, we also investigated whether certain clinical factors were associated with cognitive impairment.

Participants
The study included 84 consecutive patients evaluated from July 5,

Neuropsychological assessment
The neuropsychological study was carried out on patients who pre- In addition to cognitive measures, patients were administered the Hospital Anxiety and Depression Scale (HADS; Zigmond & Snaith, 1983) as a brief measure for anxiety and depression levels in patients.

ANALYSIS
Individual raw scores from each test were transformed into T scores according to the normative data available. T scores were then transformed into percentiles (Pc) and classified according to the ranges proposed by American Academy of Clinical Neuropsychology (Guilmette et al., 2020). The classification is the following: exceptionally high score: Pc > 98; above average score: Pc 91-97; high average score: Pc 75-90; average score Pc: 25-74; low average score: Pc 9-24; below average score: Pc 2-8; exceptionally low score: Pc < 2. Then, we classified individual test scores for each test according to these three main categories: (a) below average score and exceptionally low score (Pc < 8), low average score (Pc: 9-24), and average or above (Pc > 25).
First, we performed an analysis that aimed to describe the frequency of presence or absence of cognitive deficits according to the neuropsychological test scores as a function of the three categories, such as being a below average score/exceptionally low score, low average score, and average or above (Pc > 25). The distribution of test scores was analyzed by grouping them in cognitive domains. To define said cognitive domains, we ran a principal component analysis (PCA) that included the entire test scores (see Table 1 and Figure 1)  Finally, we performed further analyses to explore the effect of hospitalization, disease duration, biomarkers, and affective scores on cognition. Fifteen patients were treated with hydroxychloroquine (400 mg/ day) during a mean duration of 5 days and five of them were TA B L E 1 Distribution of test scores according to classification by Guilmette et al. (2020): Combined below average score and exceptionally low score (Pc < 8), low average score (Pc: 9-24), and average or above (Pc > 25)  Guilmette et al. (2020): combined below average score and exceptionally low score (Pc < 8), low average score (Pc: 9-24), and average or above (Pc > 25) also treated with Tocilizumab (400 or 600 mg). Nine patients were treated with corticosteroids for a mean duration of 6.3 days (various doses).

Distribution of test scores
Since we used several tests with many scores, we decided to reduce the number of variables by grouping them into cognitive domains. This allowed us to better describe our results in terms of cognitive processes that are affected or spared in our sample.
To define the cognitive domains implicated in this study, we ran a PCA that included the percentiles from all tests used in the neuropsy- The scores from the forward and backward digit spans showed low loadings and were not clearly associated with any of the five main factors, so we grouped them under the category "Short-Term and Working

Memory" (ST/WM). WAIS-IV Coding Test and WAIS-IV Symbol Search
were not associated with the other main factors from the PCA, so we grouped them under the category "Processing Speed.." Finally, as some of the scores on the CPT-II remained outside the main factor "Attention" but were from the same test, they were included in the same factor for the purpose of the analyses. The same reasoning was applied to the score on ROCFT -Delayed recall, which was included in the L + LTM factor.
As shown in Table 1, the amount of test scores that were suggestive of cognitive deficits (below average score and exceptionally low score,

Proportions of patients with cognitive deficits by domains
Multiple-domain impairment (60.3%) was more frequent than impairment in only one domain (39.7%) (χ 2 (1) = 5.36, p = .02). Attention deficits were the most frequent types of deficits in patients with single-domain impairment (19.0%), significantly exceeding deficits in EF (p = .01), ST/WM (p = .001), and Language (p < .001). Furthermore, attention was the cognitive domain that was most frequently impaired in conjunction with other domains in patients with multiple-domain impairment, especially with L + LTM and EF (see Figure 2).
To see whether the performance in tests assessing attention, longterm memory, and executive functions were explained by overlapping deficits, we performed correlational analyses using the composite scores derived from the T scores for the three domains. Only executive functions and attention were significantly correlated (r = .31, p = .01) (see Figure 3).

Hospitalization, disease duration, biomarkers, and affective scores
We performed further analyses to explore the effect of hospitalization, disease duration, and biomarkers on cognition.

Hospitalization
Hospitalized patients had lower MoCA scores (M = 15.8; SD = 3.8) than non-hospitalized ones (M = 17.8; SD = 2.5) (F (1, 61)) = 6.66; p < .05; age introduced as a covariate). To explore in more detail the cognitive deficits that may be associated with hospitalization, we performed group comparisons of the distributions for average score and exceptionally low score (Pc < 8), low average score (Pc: 9-24), and both combined (Pc: 0-24). The only significant group difference was found when the percentiles were combined for the Coding test (χ 2 (1) = 4.45, p = .03), suggesting that hospitalization is associated with decreased performance in processing speed (see Figure 4).

Disease duration
Correlations between individual disease durations and the compos-

Biomarkers
We correlated the composite scores of the cognitive domains with several biomarkers that have been suggested to be altered in patients with COVID-19 (Samprathi & Jayashree, 2020), including: C-reactive protein (CRP) levels, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), creatine kinase (CK), hemoglobin (Hg), platelets, leukocytes, lymphocytes, D-dimer, ferritin, F I G U R E 3 Correlation between attention, long-term memory, and executive functions F I G U R E 4 Distribution of test scores between hospitalized and non-hospitalized patients according to classification by Guilmette et al. (2020): combined below average score and exceptionally low score (Pc < 8) versus low average score (Pc: 9-24). Asterisk indicates a significant difference in test performance between groups and interleukin-6 (IL-6). Significant correlations were found only for the composite scores of Language with ferritin (r = 0.32, p = .03) and Attention with CK (r = −0.41, p = .007).

Affective scores
Correlations between anxiety and depression subscores from the HADS and all domain factors were performed. There were no significant correlations between anxiety subscores and cognitive domains.
Depression subscores only showed a significant correlation with Processing Speed (r = 0.29, p = .02), suggesting a rather weak pos-itive relationship between depression measures and this cognitive domain.

DISCUSSION
This study was conceived to further characterize the extent of cognitive impairment in post-COVID-19 patients with subjective cognitive complaints. A large US survey study found that difficulty concentrating and focusing was experienced by more than 50% of patients, being the fourth most reported long-term symptom after COVID-19 (Lambert & Corps, 2020). While cognitive impairments appear to be most pronounced in people who were hospitalized, they have also been observed in non-hospitalized patients (Hampshire et al., 2021), mild cases of COVID-19 (Townsend et al., 2020), and in asymptomatic patients (Amalakanti et al., 2021). To investigate how far-reaching the cognitive sequelae of COVID-19 are, the present study aimed to (1) provide information on the frequency of deficits in specific cognitive domains and (2) (Almeria et al., 2020;Zhou et al., 2020).  (Fuster, 2000). This finding is also in line with results from Miskowiak et al. (2021), who found a positive correlation between executive function deficits and subjective cognitive complaints in a group of COVID-19 patients assessed four months after hospitalization.
With the high frequency of low average performance in both attentional and executive control tasks, it will be essential to continue to assess this decreased performance with follow-up neuropsychological  We acknowledge that our study has some limitations, namely the absence of a control group. The ideal condition would have been to compare the cognitive performance of our sample with a healthy group of individuals without COVID-19 or a group of COVID-19 survivors without subjective cognitive complaints. However, the use of normative data allowed us to draw conclusions about the presence of cognitive deficits and lent support to the validity of our findings.
It is important to keep in mind that, given the absence of a control group without subjective cognitive complaints, our findings cannot be generalized to any patient who was diagnosed with COVID-19. Nevertheless, we believe that our results, though limited to patients with cognitive complaints, are clinically relevant for neuropsychologists assessing cognition in COVID-19 survivors.

CONCLUSION
The findings in the current study begin to shed light on the characteristics of post-COVID cognitive impairment. Specifically, assessment of patients with subjective cognitive complaints reveals high frequencies of both single-and multi-domain impact that centers upon an intertwined impairment in attention and executive functioning. Additionally, COVID-19 survivors across the spectrum of disease severity can be left with decreased cognitive function. Clinicians and researchers alike will need to address this by continuing to study post-COVID patients with comprehensive neuropsychological assessments and applying early interventions to lessen cognitive impairment.